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Transcriptional Regulation of Development in Drosophila

During development, cells maintain or change their specific identities by activating or silencing specific genes in response to the signals received from both cell-cell contacts and the environment. The interaction of the transcriptional coactivator CBP with a number of different signal-responsive transcriptional activators mediates and integrates the input from several different signaling pathways into a specific transcriptional response. CBP functions as a bridge between the activated transcription factors and the basal transcriptional machinery. In addition, it has an intrinsic acetyltransferase activity that is hypothesized to modify the chromatin surrounding the activated promoter making it more accessible to protein complexes that stimulate transcription. We have cloned Drosophila CBP (dCBP) and generated mutations in this gene in an effort to understand how the various signals are integrated at the level of transcription to elicit specific cellular responses.

Two proteins that interact with dCBP are the transcription factor cubitus interruptus that mediates hedgehog signaling during development and a SIR2-like deacetylase. The fact that dCBP has histone acetyltransferase activity suggests that this interaction may be critical for the maintenance of gene silencing during development. We are using genetic and molecular techniques to determine how these two interactions activate/silence transcription in response to various developmental signaling systems. The mutational analysis of dCBP also demonstrated that this factor is required for the S phase checkpoint of the cell cycle. These results suggest that dCBP and its mammalian counterpart may function as signal-responsive chromatin modifying proteins rather than solely as transcriptional coactivators.

Upper row of images shows a large anterior perfusion defect during acute myocardial infarction. Only a small subendocardial defect persists after successful PTCA as depicted in the lower row of images.